Cardiac Morphology in Neonates With Fetal Growth Restriction

doi:10.21203/rs.3.rs-2071958/v1

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Cardiac Morphology in Neonates With Fetal Growth Restriction

https://doi.org/10.21203/rs.3.rs-2071958/v1

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Objective: Assess effects of fetal growth restriction (FGR) on cardiac modelling in premature and term neonates.

Study design: Prospective echocardiographic cohort study comparing FGR neonates (n=21) and controls (n=41) with normal prenatal growth and circulation.

Results: Unadjusted for gestational age, birth weight, sex and twin/singleton, Late-FGR neonates had smaller hearts than controls, with globular left ventricles and symmetrical right ventricles. Adjusted estimates showed smaller left ventricles and similarly sized right ventricles, with symmetrical left and right ventricles. Early-FGR (compared with Late-FGR) had smaller hearts and globular left ventricles in unadjusted estimates, but after adjustment, sizes and shapes were similar.

Conclusion: FGR had significant impact on cardiac modelling, both unadjusted and when adjusted for gestational age, birth weight, sex and twin/singleton. The adjustments, however, refined the results notably and represents more specific the effects of FGR, thus underscoring the importance of adjustments in such studies.

perinatal circulation

cardiac modelling

cardiac remodeling

neonate

heart

echocardiography

Fetal growth restriction (FGR) is one of the major challenges in perinatal care commonly leading to premature birth, neonatal morbidity and mortality. Evidence also suggests that neonates with reduced intrauterine growth carry higher risks for metabolic and cardiovascular diseases in later life than their peers [1].

An expert consensus group has defined FGR using solitary and contributory measurements including circulatory variables and has set the cut-off between early and late FGR at 32 weeks of gestation [2].

FGR due to placental compromise affects up to ten percent of all pregnancies, depending on population, geographical location and fetal growth references in use [3]. In these cases, the fraction of combined fetal cardiac output that circulates the placenta is reduced and conditions the impaired growth [4, 5]. According to the severity of the restricted umbilical circulation, the fetus responds by redistributing its cardiac output to prioritize oxygen and nutrient supply to the heart, brain, and adrenals, the so-called centralization of the circulation. This implies a substantial downregulation of supply to other organs which takes the brunt of the fetal growth impairment.

It is plausible that such developmental challenges can permanently alter the body’s structure, function and metabolism, and increase the risk of disease in later life [6], i.e. the concept of Developmental Origins of Health and Disease [7–10]. Structural and functional cardiovascular changes in FGR fetuses have been traced into infancy, childhood, and adolescence [11–16]. Such findings could explain why low birth weight (BW) is a risk factor of cardiovascular diseases in adulthood. However, there is a knowledge gap as to what extent gestational age (GA), BW and sex influence such modifications of cardiac morphology in FGR.

Based on the hypothesis that FGR affects early postnatal cardiac morphology, this study aimed at assessing the association between FGR and cardiac morphology in premature and term neonates the first three days of life, and how GA, BW, sex and twin/singleton modify this association.

Study population and inclusion criteria

This was a prospective, observational cohort study at Oslo University Hospital, Norway between April 2017 and October 2018. We included pregnant women and their FGR neonates (GA 30–42 weeks) according to locally modified contemporary published guidelines [2] (Fig. 1), and a corresponding control group within the same range of GA but with fetal ultrasound documented normal intrauterine growth and circulation. We included singleton and dichorionic diamniotic twin pregnancies. Exclusion criteria were pregnancies with chromosomal aberrations, severe congenital anomalies, or evidence of prenatal infections.

Early-FGR (GA < 32 weeks) was defined when either 1) abdominal circumference was less than the third centile [17], 2) there was absent or reversed end diastolic flow in the umbilical artery, or 3) abdominal circumference was less than the tenth centile and pulsatility index in the umbilical or uterine arteries were above the 95th centile [18].

We defined Late-FGR (GA > 32 weeks) when two of the three following criteria were present; abdominal circumference less than the tenth centile, impaired growth rate by abdominal circumference or estimated fetal weight crossing two of the following centiles on National Fetal Growth Reference: 2.5, 5, 10, 25, 50, 75, 90, 95 and 97.5 [17, 19] with more than two weeks interval, or cerebro-placental ratio less than the fifth centile [20]. Cerebro-placental ratio was defined as the pulsatility index of the middle cerebral artery divided by the pulsatility index of the umbilical artery. Additionally, fetuses with GA > 32 weeks and abdominal circumference less than the third centile were defined as FGR.

Ethics

The Hospital’s Data Protection Officer and The Regional Ethics Committee of Research, South East, Norway approved the study (2016/923D). The parents gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki [21].

Maternal and fetal baseline characteristics

As baseline maternal characteristics, we recorded age, height, pre-pregnancy weight and body mass index (BMI), nicotine-use, alcohol consumption, medication and pre-existing and medical conditions during pregnancy. We registered maternal blood pressure, early and late in pregnancy, any introduction of blood pressure medication during pregnancy and mode of delivery, and recorded all cases of preeclampsia [22]. Higher education was defined as more than fifteen years, i.e. college or university level.

Estimated fetal size was based on intrauterine ultrasound measurements of head circumference, abdominal circumference and femur length, and the corresponding percentile derived from growth charts by Johnsen et al. [17, 19] through the CSAM Partus eHealth maternity information system. Fetal circulation was assessed by determining the pulsatility index in the umbilical artery [18], the middle cerebral artery [20], ductus venosus [23] and the uterine artery [24] on both sides.

We determined GA using head circumference or femur length according to Johnsen et al. [25, 26] at the routine ultrasound examination offered nationally at gestational week 18. In the FGR group, the recordings from the last ultrasound examination prior to birth were used as basis for inclusion. The Non-FGR group had one ultrasound examination as part of the prenatal visits to the outpatient clinic as close to term as feasible.

Neonatal baseline characteristics

For baseline neonatal characteristics, we recorded GA, BW, head circumference, sex, twin/singleton and Apgar score at five minutes.

Postnatal echocardiographic assessment and off-line analyses

One neonatologist (LB) performed all the postnatal ultrasound examinations during daytime on day one, two and three as part of a more comprehensive study of the cardiovascular transitional circulation. Vivid S6 (GE Healthcare, Horten, Norway) ultrasound machine equipped with a S6-D transducer, frequency 2.4-8.0 MHz was used for all examinations. A complete sequential two-dimensional, M-mode and Doppler echocardiography was performed (from subcostal, apical, parasternal long- and short axis and suprasternal views) to exclude congenital cardiac malformations. Five to ten cardiac cycles from each view where stored for later off-line analyses. Small insignificant muscular ventricular septum defects did not disqualify from participation. We preferably examined the neonates after feeding, when they were relaxed or asleep and in a left semi-lateral supine position.

The same physician who performed the neonatal scans (LB), did the off-line analyses using EchoPac PC analysis software system version 202 (GE, Vingmed, Horten, Norway). The mean value of the three best images or cycles were analyzed for each measurement and the average value was used in the statistical analysis.

We assessed two-dimensional images of the left atrium, left ventricle, right ventricle and right atrium from the apical four-chamber view. The pulmonary valve was assessed from the parasternal view. We used two-dimensional and M-mode images to assess the diastolic diameters of the interventricular septum, the left ventricular cavity and the left ventricular posterior wall. The aortic root, aortic valve and the left atrium were also assessed using the parasternal axis recordings in M-mode [27]. We assessed the left atrium and aortic diameters to calculate the left atrium/aortic root ratio [27, 28].

The end-diastolic diameters of the atrioventricular valve orifices, the maximal area of the left and right atrium (i.e. areas at end-systole) and the mid-cavity right ventricular linear diameter [27] and the area of the right ventricle were analyzed from the apical four chamber view. Left and right ventricular septum length were considered as the distance from the apical endocardial border to the hinge point of the septal hinge of the mitral valve [29] and tricuspid valve at end-diastole. To compare the morphology between hearts of various sizes, we used end-diastolic left ventricle septum length as a surrogate measure for heart size [29]. We normalized other heart size measurements by dividing by this septum length, and denoted normalized heart size measurements as heart size indices.

Statistical analysis

FGR neonates were divided into Early-FGR and Late-FGR according to the inclusion criteria. Within the allotted study period, it turned out to be no inclusions below 34 weeks in the Non-FGR group justifying an adjusted comparison with the Early-FGR. The analysis strategy was therefore shifted to compare the Late-FGR only with the Non-FGR group. In a separate analysis, the Early- and Late-FGR groups were compared.

Ten percent relative difference in echocardiographic variables was considered as clinically relevant. Based on previous studies [29, 30], power calculations showed that a sample size of 25–30 would provide 80 percent statistical power for detecting such differences with two-sided five percent p-values.

We used t-test, chi square test and independent-Samples Mann-Whitney U for analyses of independent variables, and two separate mixed-effects linear regression models for analyses of repeated continuous variables. The first mixed-effect model assessed the unadjusted effect of FGR. The second model assessed the adjusted effects of FGR when taking the effects of GA, BW, sex and twin/singleton into account as covariates. Both models included intercepts and FGR as an independent categorical fixed effect. The second model additionally included sex and twin/singleton as independent categorical fixed effects, and GA and BW as independent continuous fixed effects. Hence our model allowed for detailed adjustment of the confounding effects of GA and BW. Mixed model statistical analyses take into account the consecutive examinations for each patient. As the GA and BW correlated at a higher level (0.91) than our pre-selected threshold for collinearity (0.75), we were unable to assess the separate effects of BW and GA on the measurements. We present variable estimates as Estimated Marginal Means. For Estimated Marginal Means in the second model, the software used the average values for each of the continuous covariates. The software used GA 38 weeks and BW 2.8 kg in the comparisons of Estimated Marginal Means between Late-FGR and Non-FGR, and correspondingly 35 weeks and 1.9 kg in the comparisons between Early-FGR and Late-FGR. Estimated Marginal Means were hence estimates of the averaged value for the repeated measurement. We used two-sided tests, 95 percent confidence intervals and five percent p-values for all tests, and IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, N.Y., USA) for all analyses.

Clinical and baseline characteristics data

The 62 women gave birth to 69 neonates; 28 FGR (7 Early-FGR and 21 Late-FGR) and 41 Non-FGR. Seventeen of the FGR (30%) and 39 Non-FGR (70%) had gestational age ≥ 34 weeks.

The number of days from the last prenatal ultrasound examination to delivery was median 6 days (interquartile range 2–21); 2 days (1–4) for the FGR group (Early-FGR median 3 days (interquartile range (0–4), Late-FGR median 2 days (interquartile range 1–4)), and 18 days (7–29) for the Non-FGR group.

Figure 1 shows the distribution within the different FGR inclusion criteria where Late-FGR was dominating. Nearly 50% of the study group had intrauterine signs of circulatory compromise, five in the Early- (71%) and eight in the Late-FGR (38%) group. Signs of circulatory compromise was based on elevated pulsatility index in the umbilical or uterine artery, or absent or reversed diastolic flow (ARDF) in Early-FGR, and low cerebroplacental ratio in the Late-FGR group.

We included seven pairs of dichorionic, diamniotic twins. In two pairs, both twins were FGR. Three pairs consisted of one FGR and one Non-FGR. In the remaining two pairs, both were Non-FGR. All twins were premature except for one pair of Non-FGR twins. For analyses of baseline characteristics, we assigned a mother of twins to the FGR group if at least one twin was FGR. Thus, we classified 26 mothers in the FGR group and 36 in the Non-FGR group.

Concerning baseline characteristics (Table 1), the fraction of mothers with higher education was substantial in both groups. Eight mothers were diagnosed with preeclampsia according to Norwegian guidelines based on the ICD-10 criteria [22]. All of them were in the FGR group. None of the mothers had anemia or clinically relevant bacterial or viral infections. None of the mothers smoked daily and 57 never smoked.

Mean time from delivery to first echocardiography was 25 hours (SD 8). Mean time from delivery to second echocardiography was 47 hours (SD 7) and to third echocardiography 71 hours (SD 8).

The FGR neonates had significantly lower GA, BW, and head circumference than the Non-FGR neonates (Table 1). Sex and Apgar score at 5 minutes were equal. Only four (14%) in the term Non-FGR group (n = 29), but seven (58%) in the premature Non-FGR group (n = 12) were born after caesarean section. Of the 13 born after caesarean section in the Late-FGR group, nine (69%) were premature. The frequency of caesarean section was higher in both FGR groups than in the Non-FGR group. Only neonates who were either premature or suffered from FGR needed admission to the Neonatal Intensive Care Unit. All neonates admitted to the Neonatal Intensive Care Unit survived to discharge and none of them were at any time critically ill.

Cardiac morphology

We conducted 189 postnatal ultrasound examinations on day one, two and three. Eighteen examinations were missing due to logistical reasons.

All reported echocardiographic measurements were performed at end-diastole except the maximal area of the left and right atrium that were measured at end-systole.

Neonates exposed to Late-FGR had generally smaller hearts as all unadjusted left and right sided measurements including the interventricular septum diameter were lower than in their Non-FGR peers (Table 2).

After adjustment, the left ventricular septum length, diameter of the left atrium, aortic valve and the left ventricle internal diameter remained smaller in Late-FGR (Table 2). On the right side of the heart, the pulmonary valve diameter and the right ventricular diameter remained smaller (Fig. 2).

The left columns of Table 3 show the same measurements normalized for heart size by dividing the measurement by the left ventricular septum length, unadjusted and adjusted for GA, BW, sex and twin/singleton. The unadjusted indices of the left side of the heart were similar between groups except for larger mitral valve in the Late-FGR group compared with Non-FGR. For the unadjusted right sided indices, the groups were similar except for the right atrial and ventricular area which was smaller in Late-FGR than in Non-FGR.

The adjusted left and right sided indices for Late-FGR were similar to those in Non-FGR.

Ratios between the corresponding right and left sided measurements were similar for the unadjusted indices except for a lower right ventricular mid-wall to left ventricular internal diameter ratio in the late FGR group compared with Non-FGR. The adjusted indices were also similar, except for a lower ratio of tricuspid to mitral valve diameters in the adjusted Late-FGR group compared with Non-FGR.

When comparing the Early-FGR with the Late-FGR group (columns to the right in Table 2), all the unadjusted measurements were smaller in the Early-FGR group except for the left atrial to aortic diameter ratio. When adjusting for GA, BW and sex/singleton, there were no differences between the groups.

When normalizing for heart size, the left and right atrial areas and right ventricular area indices were smaller for unadjusted measurements in Early-FGR compared with Late-FGR, whereas the intraventricular septum and left ventricular diameter indices were larger in Early-FGR. After adjustment the left atrial area index remained smaller and the intraventricular septum remained thicker. There were no differences when comparing corresponding left and right sided measurement for unadjusted or adjusted measurements.

Sex and singleton/twins had no impact on any of the measurements or indices (Tables 2 and 3).

The effect of adjusting for relevant factors was notable as visualized in Fig. 2. Nine significant differences in unadjusted measurements were rendered insignificant by the adjustment (Table 2). Similarly, among the 14 established ratios of intracardiac proportions (Table 3), four significant findings were rendered not significant, and vise-versa, one not significant ratio became significant.

Our main findings were that Late-FGR neonates had smaller hearts with a globular shape compared with Non-FGR neonates the first three postnatal days. By adjusting for BW, GA, sex and whether they were twins or singletons, we identified genuine effects of Late-FGR as shown in Fig. 2, i.e., the left ventricle was small and symmetrical while the right ventricle was symmetrical with a similar length to that of normally grown neonates.

Similarly, we found generally smaller hearts with a globular left ventricle, thicker intraventricular septum and smaller atrial areas for the Early-FGR group compared with the Late-FGR group. We also found that significantly smaller left atrial area and thicker intraventricular septum remained significantly different between the groups after adjusting for BW, GA, sex and twins or singletons.

Several of the differences persisted when adjusting for GA, BW, sex and singleton/twins when comparing Late-FGR with Non-FGR. Hence, our study showed that Late-FGR per se was an important determinant for heart morphology. It also showed that adjusting for GA and BW modified the impact of FGR. There was strong collinearity between GA and BW (correlation coefficient > 0.9), preventing us from distinguishing the separate effects of GA and BW.

We found shorter length of the left ventricle both in Early-FGR compared to Non-FGR and Early-FGR compared with Late-FGR, which is in accordance with other studies [14, 31]. Several studies support our findings that both term and premature FGR neonates had smaller diameter of the left ventricle [14, 31–33]. Most studies have examined mainly the left ventricle, while Patey et al. [14] also studied the right ventricle in their term FGR group. Their findings were in accordance with ours, showing a significantly lower right ventricle diameter in Late-FGR.

Several studies have demonstrated a globular cardiac morphology following FGR [13, 31, 34, 35], which confirms our findings that prenatal alterations in ventricular shape are found postnatally following FGR. While none of these studies adjusted for GA, BW, sex and singleton/twins, we found that adjusted ventricle dimensions were symmetrical and exhibited a symmetrical shape. However, the lower adjusted tricuspid-mitral diameter ratio, the lower diameter but similar length of the right ventricle, and the strong trend of a smaller right ventricle at mid-wall (p = 0.053), indicate a tendency towards a slim right neonatal ventricle after late FGR. This is plausible as the prenatal function during FGR loads the right ventricle with a disproportionate larger output than the left [4]. After birth the right output comes down to match the left side; the transverse diameter is correspondingly reduced whereas the length of the right ventricle is maintained. Crispi et al. [6] and Rodriguez-Lopez et al. [36] have suggested elongated, globular and hypertrophic fetal cardiac phenotypes depending on the level of severity of FGR as a consequence of adaptive cardiovascular modelling. Hearts develop a spherical shape to maintain stroke volume in presence of pressure overload. In the elongated phenotype, one ventricle develops a spherical shape and the other consequently becomes elongated, and in the globular phenotype both ventricles develop a spherical shape. Our findings suggest an elongated phenotype and that our Late-FGR group was at a mild-to-moderate stage of morphological compensation. The increased tricuspid valve/mitral valve ratio when adjusting for GA, BW, sex and twin/singleton was also shown in the study by Patey et al. [14]. However, unlike their study, we found a lower ratio of unadjusted right-to-left ventricle diameters in the Late-FGR group compared with the Non-FGR group. Our groups consisted of premature and term neonates whereas in the study by Patey el al, all were born at term.

As we found lower diameter of the interventricular septum in the Late-FGR group in unadjusted estimates and similar diameter in adjusted estimates, difference in interventricular septum diameter was probably due to differences in these covariates between groups. Cohen et al. [35] found no difference in left ventricle wall thickness on day one when adjusting for body surface area, and Ciccone et al. [37] found that the differences in diameter in interventricular septum and left ventricular posterior wall disappeared when normalized for body surface area in both term and premature Non-FGR neonates. Some studies report thinner ventricle septum in FGR [32, 33], whereas others report opposite findings [13, 31]. Differences in study design and inclusion criteria might explain these differences. Crispi et al. [6] regarded hypertrophy as a late sign of cardiovascular modeling in symmetric FGR, following hypoxic incidents occurring early in the pregnancy. As the majority of our FGR neonates were late, asymmetric FGR, interventricular septum and left ventricle posterior wall hypertrophy may not yet have evolved. Another significant factor may be variations in the definitions of FGR. We based our definition of FGR on contemporary criteria by use of fetal assessment [2]. As others studies have used definitions based solely on estimated fetal centiles [31] or confirmed BW [13], our study groups may not be directly comparable with such studies. We also speculate whether different clinical practices concerning timing of delivery affected the postnatal condition of neonates following FGR [38].

The Early-FGR group had smaller hearts than the Late-FGR group and a globular shape of the left ventricle in the unadjusted estimates, whereas adjusted estimates revealed few differences in size and shape between the groups.

FGR is associated with a risk of a differently modelled cardiovascular system in the years following birth [11, 13, 31, 34, 35]. However, less is known to what extent these changes are linked to disease development later in life, something that awaits results of correspondingly designed long-term observational studies.

A strength of our study was the prenatal inclusion criteria. We defined FGR based on contemporary published guidelines [2], and the control group had verified normal prenatal growth and circulation. Several definitions of FGR and small for GA exists [39, 40]. Sometimes the terms are used interchangeably [41], probably contributing to the heterogeneity of findings in this field. Due to the criteria of fetal growth less than a certain centile, both constitutionally small neonates and neonates with true FGR may be included. Only three of our fetuses were included on AC diameter less than the third centile alone. The others had reduced growth and/or centralized circulation. We recruited the pregnant women and their fetuses unselected from our ordinary outpatient clinic. They represent everyday life in a regular university tertiary center, and our inclusion criteria reflect contemporary published guidelines [2] but with local hospital adjustments. The same neonatologist did all the postnatal ultrasound examinations and all off-line analyses eliminating inter-rater variability.

We included the pregnant women in the term Non-FGR group from a unit of only low risk deliveries. They therefore represented a particularly healthy group of the pregnant population possibly reducing the external validity of our study. However, the mothers of the FGR group combined and the Non-FGR group were similar regarding educational level and presence of non-pregnancy risk factors.

We had insufficient inclusions of Non-FGR with low gestational age to carry out comparison with the Early-FGR group. It was difficult to identify and foresee premature delivery in women with documented normal prenatal circulation and growth. In general, selection bias is a challenge, which applies also to the present study, particularly the premature Non-FGR group since there is a probability that premature birth is related to pathology. Their generally uneventful course to discharge, however, was reassuring that these participants functioned appropriately as control group.

We chose to include dichorionic, diamniotic twin pregnancies because they have separate placentas and could act as each other’s controls. One could argue that their circulation is not completely independent. However, twin pregnancies are an important part of the FGR-population. By including them we improved external validity. Besides, we adjusted for singleton/twins in the statistical analysis.

Adjusting for repeated measurements, GA and BW is usually a relevant refinement, but concerns may be raised when the compared groups in the statistical model differ substantially in these characteristics. In our case, the Non-FGR group had no inclusion below 34 weeks that could match the Early-FGR group (Fig. 1b). We therefore focused on the Late-FGR group to compare with the Non-FGR group, and conducted a separate comparison between Early- and Late-FGR, without control group. Due to low numbers, this latter comparison had a restricted power to detect but clear differences. We acknowledge the fact that Early-FGR conventionally represents a more sinister disease profile that rarely permits the pregnancy to reach term in contrast to Late-FGR. One might therefore expect more pronounced cardiac alterations in Early- than Late-FGR and a potential skewed adjustment when included in the same group.

This study showed that FGR significantly impacts neonatal cardiac morphology. Late-FGR neonates had smaller hearts, a globular shaped basis most prominent on the left side, and symmetrical right ventricle. When adjusted for GA, BW, sex and twin/singleton, we found smaller left ventricles and similarly sized right ventricles, with symmetrical shapes. Interventricular septum diameters were similar. Unadjusted estimates showed smaller hearts, thicker intraventricular septum and globular left ventricles in Early-FGR compared with Late-FGR, whereas adjusted estimates of sizes and shapes were similar. This underscores the importance of adjusting for relevant factors when assessing the genuine effects of FGR.

ACKNOWLEDGEMENTS:

We thank the parents and their neonates that participated in this study, and to the hospital staff for facilitating the study. We acknowledge the assistance received from Dr. Henrik Husby and Dr. Tom Hartgill for participation in patient recruitment and prenatal data acquisition and valuable advice in the planning of the study. Thanks to Polona Rajar for help with the cardiac illustration.

AUTHOR CONTRIBUTION:

LB was responsible for investigation, writing – original draft, formal analysis, writing, visualization, review & editing. DF was responsible for conceptualization of the study, methodology, writing – original draft, formal analysis, writing, review & editing and supervision. NH was responsible for investigation, writing, and review & editing. TK was responsible for conceptualization of the study, methodology, writing, and review & editing. GH was responsible for conceptualization of the study, methodology, writing, review & editing and supervision. EN was responsible for conceptualization of the study, methodology, writing – original draft, formal analysis, writing, review & editing and supervision.

FUNDING

The research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors. This study is part of a PhD project funded by the University of Oslo.

COMPETING INTERESTS

The authors declare no competing interests.

ADDITIONAL INFORMATION

Correspondence and requests for materials should be addressed to Eirik Nestaas.

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Table 1-3 are available in the Supplemental Files section.

There is NO conflict of interest to disclose.

CardiacMorphologyTable1Clinicalandbaselinecharacteristics20220913.pdf
Table 1
CardiacMorphologyTable220220913.pdf
Table 2
CardiacMorphologyTable320220913.pdf
Table 3

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Cardiac Morphology in Neonates With Fetal Growth Restriction

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Abstract

Figures

Introduction

Methods

Study population and inclusion criteria

Ethics

Maternal and fetal baseline characteristics

Neonatal baseline characteristics

Postnatal echocardiographic assessment and off-line analyses

Statistical analysis

Results

Clinical and baseline characteristics data

Cardiac morphology

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1